Cancers of the foregut (hepatocellular, gastric and pancreatic) are lethal and difficult to treat due to late diagnosis, few viable targeted therapeutics and unclear molecular profiling of each stage of tumon development, from metaplasia to dysplasia to carcinoma. Recent studies support a key role for TGF-B signaling in suppressing these tumors, yet its mechanism of action and the specific stages at which it is important remain unclear. The Smad3/4 adaptor protein ELF is a powerful effector of TGF-B tumor suppressor function. We previously found that deletion of ELF results in a dramatic and spontaneous formation of liver (HCC) and gastrointestinal (GI) cancers, with exon 15 mutations in 11% of human HCC and gastric cancer cell lines tested so far. Elf[+/-] and elf[+/-]/Smad3[+/-] mice develop visceromegaly and multiple Gl cancers (70% of mice), including metastatic pancreatic, HCC, intestinal adenocarcinomas and others spontaneously. This phenotype provides compelling evidence that elf[+/-] and elf[+/-]/Smad3[+/-] mice are a model of the hereditary human cancer syndrome, Beckwith-Wiedemann (BWS). High levels of cell cycle regulators including CDK4, c-Myc, h-TERT, B-catenin, and the E3 ligase PRAJA occur in tumors in these animals. The overall hypothesis of this P01 application, is that disruption of the TGF-B tumor suppressor pathway (through ELF, Smad3 and Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of pathways that include the wnt pathway (B-catenin), cell cycle regulators such as CDK4, c-Myc, telomerase, E3 ligases that include PRAJA and others, resulting in gastrointestinal cancers. This PO1 proposes to 1) Use animal models that have predetermined mutations in specific pathways that include wnt, TGF-B, myc, telomerase (TERT), CDK4 to determine their role in BWS and foregut cancer formation;2) Develop markers and targeted therapeutics to these lethal human cancers. Project 1, Dr. L. Mishra, utilizing a mouse model system, plans to find out how cross talk between TGF-beta signaling and cell cycle proteins (CDK4) and the E3 ligase PRAJA modulate foregut tumor suppression and to determine the potential role of ELF/Smads as functional new markers for the detection and treatment response of BWS and human gastrointestinal (GI) cancers. Project 2. Dr. S. Byers plans to characterize the role of activated (B-catenin/TCF in the mouse model systems above, and develop a therapeutics strategy to human cancers with Vitamin D analogs which will also be utilized in Project 1, 3 and 4. In Project 3, Drs. R. Schlegel and B. Mishra, plan to determine the role of ELF and Smad3 in modulation of human TERT and c- Myc in cancers of the foregut, and translate these studies with Projects 1, 2 and 4 in terms of human markers and treatment strategies. Project 4 by Dr. E. P. Reddy, aims to determine the role of CDK4 in foregut cancers with transgenic model systems and initiate the development of small-molecule CDK inhibitors of CDK4 for therapy that will be utilized in Projects 1, 2 and 3. The program will be logistically supported by three cores: an Animal Core (A), a Cell and Tissue Core (B), and an Administrative Core (C). The cores will enable efficient cooperation and cost savings essential for all the research projects. The studies proposed under this Program Project should provide the scientific community with a better understanding of the mechanisms that regulate foregut cancer development. Significantly, this program promises to yield new therapies targeted at these difficult-to-treat lethal cancers at the bench, and then to translate the results rapidly into clinical care, at the bedside.